Abstract Malarial remains a global health burden that impacts >40% of humans. Although bed nets and antimalarial drugs have reduced the incidence and severity of malaria, ~200,000,000 cases still occur annually with high mortality in children from sub-Saharan Africa. Additionally, front line drug therapies are now threatened by spread of resistant parasites. Thus, new approaches to effective vaccines and therapeutics are in need. A critical limitation is our incomplete understanding of how the parasite manipulates host immune responses to permit chronic and recurring blood-stage infections. We used rodent malaria models to evaluate the cellular dynamics of the CD4 T cell and B cell responses generated during chronic blood-stage infection and then compared these findings to humans living in endemic areas. These studies reveal that Tregs, which expand in both humans and rodents during blood-stage malaria, interfere with conventional T helper (Th) responses and the Follicular T helper (Tfh) cell:B cell partnership in germinal centers. Importantly, the negative impact of Tregs occurs in a previously unrecognized but critical temporal window after infection to impede protective immunity, through CTLA-4. Precisely timed targeting of Tregs or CTLA-4 enhanced immune responses, accelerated clearance, and generated species-transcending immunity to blood-stage malaria. Thus, our preliminary data uncover a critical mechanism of immune-suppression associated with blood-stage malaria. A full understanding of the cellular and molecular basis for compromised immunity in blood-stage malaria is the long-term goal of this competitive renewal application. We will address these issues with the following specific aims: SA 1: Determine how precisely timed Treg-depletion and CTLA-4 blockade impacts malaria-specific T cell and B cell responses to facilitate clearance of PRIMARY blood-stage infections. SA 2: Determine how precisely timed Treg-depletion and/or CTLA-4 blockade impacts malaria-specific memory T cell and B cell responses to facilitate species transcending control of SECONDARY blood-stage infections. SA 3: Dissect how and when inhibitory pathways and cells limit clearance of PRIMARY infection and prevent development of species transcending control of SECONDARY infections.